Synthesis of substituted estradiols by the selective aromatization of A-ring of steroidal 19-nor-Δ-4-3-ketones with phenylselenyl halides/hydrogen peroxide

Article abstract of DOI:10.1016/j.steroids.2013.03.005

A range of 6-, 7-, and 11-substituted estradiols were synthesized by the selective aromatization of the A-ring of 19-nor steroids using phenylselenyl halides followed by oxidation with hydrogen peroxide. Established methods utilizing copper(II) halides failed or have given poor yields with these substrates.

Full text of DOI:10.1016/j.steroids.2013.03.005

Steroids 78 (2013) 707–710
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Steroids
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Synthesis of substituted estradiols by the selective aromatization of A-ring of
steroidal 19-nor-D-4-3-ketones with phenylselenyl halides/hydrogen peroxide
⇑
Bindu Santhamma , Klaus Nickisch
Evestra Inc., San Antonio, TX, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A range of 6-, 7-, and 11-substituted estradiols were synthesized by the selective aromatization of the A-
ring of 19-nor steroids using phenylselenyl halides followed by oxidation with hydrogen peroxide. Estab-
lished methods utilizing copper(II) halides failed or have given poor yields with these substrates.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 16 October 2012
Received in revised form 14 March 2013
Accepted 23 March 2013
Available online 9 April 2013
Keywords:
Substituted estradiols
Aromatization
Phenylselenyl halides
1. Introduction
2. Experimental
Estrogens are a class of physiologically active steroid molecules
that play a crucial role in reproduction as well as in the mainte-
nance of normal human physiology. Their widespread uses as
pharmaceutical agents in hormonal birth control, hormone
replacement therapy and for other gynecological indications make
their synthesis attractive to date [1–4]. One of the key steps in the
total synthesis of estrogens is the aromatization of the A-ring. A
variety of methods are reported in the literature for the A-ring aro-
matization of 19-nor steroids, which spans from microbiological
[5] to chemical methods, namely selenium dioxide and copper bro-
mide [6,7]. As a part of an ongoing project for the development of
new estrogens, we had to accomplish the selective aromatization
of a number of highly substituted 19-nor steroids. Most of the con-
ventional methods, however, failed or gave very poor yields when
applied to our substrates. Herein we describe our efforts in the
selective A-ring aromatization of 6-, 7-, and 11-substituted 19-
nor steroids using a combination of phenylselenyl halides and
hydrogen peroxide. Although the use of this methodology has been
reported in the literature for the transformation of 19-nor testos-
terone to estrone [8], it gained very limited attention in steroid
chemistry. We have investigated the scope and use of this reagent
combination in the selective aromatization of a number of highly
substituted 19-nor steroids where the standard methods failed
and our results are summarized below.
General: NMR spectra were recorded at 300 (1H) and 75
13C) MHz, respectively, on a Bruker ARX-300 MHz NMR spectrom-
(
eter. Chemical shifts (d) are reported relative to TMS (1H) and
CDCl3 (13C) as the internal standards. Coupling constants (J) are re-
ported in Hertz (Hz). High-resolution mass spectral analysis was
conducted on an Agilent 6224 ESI–TOF mass spectrometer with
sample introduction by infusion. Melting points were recorded
on a MEL-TEMPÒ 3.0 melting point apparatus and are uncorrected.
Infrared spectra were recorded on a Thermo-Nicolet AVATAR 370
FT-IR machine. ‘Flash column’ chromatography was performed on
32–64-lm silica gel obtained from EM Science (Gibbstown, NJ).
Thin-layer chromatography (TLC) analyses were carried out on sil-
ica gel GF (Analtech) glass plates (2.5 cm  10 cm with 250
lm
layer and pre-scored). Most chemicals and solvents were analytical
grade and used without further purification. Commercial reagents
were purchased from Aldrich Chemical Company (Milwaukee, WI).
All experiments were carried out under inert atmosphere using dry
nitrogen. For reactions that gave known compounds, the products
were compared with reported spectroscopic data.
2.1. Synthesis of starting materials
All starting materials were prepared according to reported liter-
ature procedures. Compound 1 was synthesized from the known 3-
methoxy-11b, 17b-dihydroxy estra-1,3,5(10)-tirene by a Birch
reduction [9], benzylation of 11 and 17 hydroxyl groups followed
by acid hydrolysis [10]. Compounds 3a, 3b, 3c, 3d[11], 5[12] and
7[13] were synthesized following reported procedures. Compound
⇑
Corresponding author. Tel.: +1 2106733300x116.
E-mail address: bsanthamma@evestra.com (B. Santhamma).
0039-128X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2013.03.005

708
B. Santhamma, K. Nickisch / Steroids 78 (2013) 707–710
4a is a known compound and spectral data were found to be
matching [14].
1603, 1251, 1087, 827. 1H NMR (d, 300 MHz, CDCl3) 0.02 and
0.04 (2s, 6H, –Si(CH3)2, 0.80 (d, J = 7 Hz, 3H, –CH3), 0.89 (m, 12H,
4Â –CH3), 3.60 (t, J = 8.5 Hz, 1H, –CHO), 6.57 (m, 1H, –ArH), 6.66
(dd, J1 = 3 Hz, J2 = 6 Hz, 1H, –ArH), 7.01 (d, J = 8.4 Hz, 1H). 13C
NMR (75 MHz, CDCl3) À4.8, À4.5, 15.1, 17.3, 18.1, 23.4, 25.9,
26.9, 30.2, 30.5, 30.9, 36.7, 43.7, 45.0, 51.3, 83.0, 91.9, 113.2,
115.4, 127.9, 129.7, 138.9, 153.8. HRMS calculated for C25H39O2Si
(M/ZÀH) 399.2718. Found 399.2719.
2.2. General procedure for the aromatization reaction
2.2.1. 11b,17b-Dibenzyloxy estra-1,3,5 (10)-triene-3-ol (2)
A solution of compound 1 (1 g, 2.12 mmol) in anhydrous THF
(10 mL) was cooled to À78 °C and was treated dropwise with a
1 M THF solution of lithium bis(trimethylsilyl)amide (LiHMDS)
(4.24 mL, 4.24 mmol). The resulting solution was stirred at
À78 °C for 1.5 h. A solution of phenylselenyl chloride in anhydrous
THF (10 mL) was added to the reaction mixture at À78 °C and was
stirred for 3 h with warming to 0 °C. TLC showed complete conver-
sion of starting material to the product. The reaction was quenched
by the addition of saturated ammonium chloride (20 mL) and was
extracted with EtOAc. The combined organic layers were washed
with water, brine and were dried over anhydrous sodium sulfate.
The solvent was removed in vacuo to afford crude 1a as a dark
brown viscous liquid (1.25 g). The crude 1a thus obtained was dis-
solved in THF (20 mL) and was treated with 30% hydrogen perox-
ide solution (0.5 mL, 4.24 mmol). The reaction mixture was
stirred at room temperature for 3 h and was quenched by the addi-
tion of saturated Na2S2O3 solution. The reaction mixture was ex-
tracted with EtOAc (2 Â 30 mL) and the combined organic layers
were washed with water, brine and dried over anhydrous sodium
sulfate. The solvent was removed in vacuo to give crude 2 (1 g)
as a dark brown solid, which was purified by chromatography on
a silica column eluting with 20% EtOAc–hexane solvent system.
This gave the pure compound 2 as a pale yellow solid (530 mg,
53%) m.p. 152–153 °C IR (cmÀ1) 3303, 2871, 1582, 1099, 1041, 701.
1H NMR (d, 300 MHz, CDCl3) 1.10 (s, 3H, –CH3), 3.48 (t,
J = 8.4 Hz, –CHO), 4.28 (m, 1H, CHO), 4.36 (d, J = 11.7 Hz, 1H, –
OCH2), 4.58 (m, 3H, –OCH2), 4.68 (s, 1H, –OH), 6.53 (m, 2H, ArH),
6.81 (d, J = 7.9 Hz, 1H, –ArH), 7.17 (m, 2H, ArH), 7.28 (m, 4H, –
ArH), 7.37 (m, 4H, –ArH). 13C NMR (75 MHz, CDCl3) 13.3, 23.0,
27.2, 27.7, 29.7, 33.6, 38.6, 43.3, 49.5, 51.2, 59.4, 70.4, 71.6, 74.0,
88.7, 112.6, 115.5, 127.4, 127.5, 128.0, 128.3, 129.2, 138.4, 138.9,
139.3, 152.9. HRMS calculated for C32H35O3 (M/ZÀH) 467.2586.
Found 467.2632.
2.2.4. 17b-tert-Butyldimethylsilyloxy,7a,11b-dimethyl-estra-
1,3,5(10)-triene-3-ol (4c)
Compound 4c was prepared from 3c in 69% yield following the
general procedure described for 2 except phenylselenyl bromide
was used in place of phenylselenyl chloride and the following
amounts of reagents were used: 3c (353 mg, 0.85 mmol), phenyl-
selenyl bromide (401 mg, 2 mmol), LiHMDS (2.6 mL, 2.6 mmol),
30% hydrogen peroxide (0.13 mL, 1.1 mmol). The product was puri-
fied using a silica column eluting with 10% EtOAc–hexane solvent
system. 4c: 180 mg, white crystalline solid. m.p. 179–181 °C. IR
(cmÀ1) 3307, 2900, 1502, 1246, 1112, 839. 1H NMR (d, 300 MHz,
CDCl3) 0.03 (2s, 6H, –Si(CH3)2), 0.80 (d, J = 7 Hz, 3H, –CH3), 0.85
(m, 6H, 2Â –CH3), 0.9 (s, 9H, 3Â –CH3), 3.62 (t, J = 8.1 Hz, 1H, –
CHO), 6.52 (m, 1H, –ArH), 6.62 (dd, J1 = 3 Hz, J2 = 6 Hz, 1H, –ArH),
7.03 (d, J = 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) À4.7, À4.5,
12.3, 15.0, 17.4, 18.1, 22.7, 25.9, 27.7, 30.8, 30.9, 35.8, 38.2, 42.5,
43.9, 44.9, 45.7, 48.2, 83.0, 113.0, 116.0, 127.9, 130.0, 137.6,
152.9. HRMS calculated for C26H41O2Si (M/ZÀH) 413.2876. Found
413.2874.
2.2.5. 13b-Ethyl-11-methylene-18-nor-estra-1,3,5(10)-triene-3,17b-
ol (6a)
Compound 6a was prepared from 5a in 59% yield following the
general procedure described for 2 except phenylselenyl bromide
was used in place of phenylselenyl chloride and the following
amounts of reagents were used: 5a (460 mg, 1.5 mmol), phenylsel-
enyl bromide (722 mg, 3.1 mmol), LiHMDS (7.7 mL, 7.7 mmol), 30%
hydrogen peroxide (0.17 mL, 1.5 mmol). The product was purified
using a silica column eluting with 30% EtOAc–hexane solvent sys-
tem. 6a: 260 mg, pale yellow amorphous solid. IR (cmÀ1) 3320,
2938, 1616, 1288, 1058, 801. 1H NMR (d, 300 MHz, CDCl3) 1.07 (t,
J = 7.5 Hz, 3H, –CH3), 3.93 (t, J = 7.9 Hz, 1H, –CHO), 4.74 (bs, 1H, –
OH), 4.87 (s, 1H, @CH), 4.98 (s, 1H, @CH), 6.58 (s, 1H, –ArH), 6.63
(dd, J1 = 3 Hz, J2 = 6 Hz, 1H, –ArH), 7.21 (d, J = 8.2 Hz, 1H, –ArH).
13C NMR (75 MHz, CDCl3) 9.2, 18.8, 22.0, 26.8, 30.7, 31.3, 41.6,
44.3, 47.2, 51.3, 52.2, 83.3, 109.0, 112.4, 115.4, 127.9, 131.4,
2.2.2. 11b-Methyl-estra-1,3,5(10)-triene-3, 17b-diol (4a)
Compound 4a was prepared from 3a in 60% yield following the
general procedure described for 2 except phenylselenyl bromide
was used in place of phenylselenyl chloride and the following
amounts of reagents were used: 3a (288 mg, 1 mmol), phenylsele-
nyl bromide (472 mg, 2 mmol), LiHMDS (5 mL, 5 mmol), 30%
hydrogen peroxide (0.17 mL, 1.5 mmol). The product was purified
using a silica column eluting with 30% EtOAc–hexane solvent sys-
tem. 4a: 170 mg, pale yellow amorphous solid. IR (cmÀ1) 3336,
2908, 1616, 1246, 1058, 822. 1H NMR (d, 300 MHz, CDCl3) 0.88
(m, 6H, 2Â –CH3), 3.71 (m, 1H, –CHO), 4.68 (s, 1H, –OH), 6.54 (m,
1H, –ArH), 6.63 (dd, J1 = 2.7 Hz, J2 = 5.7 Hz, –ArH), 7.05 (d,
J = 8.3 Hz, –ArH). 13C NMR (75 MHz, CDCl3) 14.8, 17.3, 23.2, 26.8,
30.1, 30.4, 30.5, 33.8, 43.4, 44.4, 48.9, 51.6, 83.1, 112.9, 115.2,
128.1, 130.4, 139.1, 152.9.
139.5, 147.5, 153.2. HRMS calculated for
297.1855. Found 297.1860.
C
20H25O2 (M/ZÀH)
2.2.6. 13b-Ethyl-11-methylene-18,19-dinor-17a-pregna-1,3,5(10)-
triene-20-yne-3,17b-ol (6b)
Compound 6b was prepared from 5b in 84% yield following the
general procedure described for 2 except phenylselenyl bromide
was used in place of phenylselenyl chloride and the following
amounts of reagents were used: 5b (324 mg, 1 mmol), phenylsele-
nyl bromide (472 mg, 2 mmol), LiHMDS (5 mL, 5 mmol), 30%
hydrogen peroxide (0. 22 mL, 2 mmol). The product was purified
using a silica column eluting with 40% EtOAc–hexane solvent sys-
tem. 6b: 270 mg, pale yellow amorphous solid. IR (cmÀ1) 3301,
2940, 2245, 1611, 1246, 1053, 905. 1H NMR (d, 300 MHz, CDCl3)
1.06 (t, J = 7.2 Hz, 3H, –CH3), 2.05 (s, 1H), 3.03 (d, J = 10 Hz, 1H),
4.72 (s, 1H, –OH), 4.88 (s, 1H, @CH), 5.00 (s, 1H, @CH), 6.56 (d,
J = 2.6 Hz, 1H, –ArH), 6.63 (dd, J1 = 2.6 Hz, J2 = 6 Hz, 1H, –ArH),
7.21 (d, J = 8.4 Hz, 1H, –ArH). 13C NMR (75 MHz, CDCl3) 9.3, 19.9,
21.7, 26.9, 30.7, 40.0, 40.4, 42.0, 50.9, 52.1, 74.2, 81.1, 87.8, 109.2,
112.5, 115.3, 127.8, 131.3, 139.5, 147.8, 153.1.
2.2.3. 17b-tert-butyldimethylsilyloxy, 11b-methyl-estra-1,3,5(10)-
triene-3-ol (4b)
Compound 4b was prepared from 3b in 79% yield following the
general procedure described for 2 except phenylselenyl bromide
was used in place of phenylselenyl chloride and the following
amounts of reagents were used: 3b (403 mg, 1 mmol), phenylsele-
nyl bromide (283 mg, 1.2 mmol), LiHMDS (3 mL, 3 mmol), 30%
hydrogen peroxide (0. 13 mL, 1.2 mmol). The product was purified
using a silica column eluting with 10% EtOAc–hexane solvent sys-
tem. 4b: 320 mg, white amorphous solid. IR (cmÀ1) 3303, 2883,

B. Santhamma, K. Nickisch / Steroids 78 (2013) 707–710
709
Scheme 1. Synthesis of compound 2
Scheme 2. Syntheses of compounds 4a, 4b and 4c
Scheme 3. Syntheses of compounds 6a and 6b
2.2.7. 17b-tert-Butyldimethylsilyloxy, 6,6-cyclopropyl-estra-1,
3,5(10)-triene-3-ol (8)
Compound 8 was prepared from 7 in 37% yield following the
general procedure described for 2 except phenylselenyl bromide
was used in place of phenylselenyl chloride and the following
amounts of reagents were used: 7 (580 mg, 1 mmol), phenylselenyl
bromide (396 mg, 1.2 mmol), LiHMDS (3 mL, 3 mmol), 30% hydro-
gen peroxide (0. 23 mL, 2.1 mmol). The product was purified using
a silica column eluting with 40% EtOAc–hexane solvent system. 8:
210 mg, pale yellow amorphous solid. IR (cmÀ1) 3362, 2921, 1620,
1251, 1099, 839. 1H NMR (d, 300 MHz, CDCl3) 0.04 (s, 3H, –
Si(CH3)2), 0.05 –Si(CH3)2), 0.77 (s, 4H, –CH2), 0.79 (s, 3H, –CH3),
0.91(s, –Si–C–(CH3)3) 3.65 (t, J = 8.1 Hz, 1H), 4.8 (bs, 1H, –OH),
6.12 (d, J = 2.5 Hz, 1H, –ArH), 6.58 (dd, J1 = 3 Hz, J2 = 5.6 Hz, 1H, –
ArH), 7.15 (d, J = 8.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) À4.8,
À4.5, 11.3, 16.7, 18.1, 18.5, 23.2, 23.5, 25.3, 25.6, 30.9, 34.7, 37.9,
39.8, 43.5, 44.7, 49.3, 81.7, 108.4, 111.9, 126.2, 133.2, 143.7,
153.8. HRMS calculated for C26H39O2Si (M/ZÀH) 411.2720. Found
411.2715.
Scheme 4. Synthesis of compound 8
ble example being etonogestrel (5b), a steroidal progestin largely
used in hormonal birth control. The A-ring aromatized etonoge-
strel derivative 6b was obtained in an excellent yield of 84%. It
should be noted that this transformation was previously achieved
only through microbial oxidation [19].
This methodology was also tried on 6-substituted 3-keto-D-4,
19-nor steroid 7. All conventional methods of aromatization failed
when applied to this substrate. As shown in Scheme 4, the corre-
sponding estradiol derivative was obtained in a moderate yield of
37%.
In conclusion, we studied the scope of using phenylselenyl ha-
lides and hydrogen peroxide for the selective A-ring aromatization
of substituted 19-nor steroids. It is also established that, this meth-
odology is substituent independent and gave moderate to excellent
yields of a variety of substituted estradiol derivatives.
3. Results and discussion
Our studies commenced with the aromatization of 11,17-diben-
zyloxy 19-nor steroid derivative 1 (Scheme 1).
As shown in the above scheme, substrate 1 was deprotonated at
C-2 with LiHMDS at À78 °C and the resulting enolate was trapped
with phenylselenyl chloride. The resulting phenylselenyl adduct
was oxidized using hydrogen peroxide to afford the 11-, 17-diben-
zyloxy estradiol derivative 2 in 53% yield. Comparable yield of 2
was obtained when phenylselenyl bromide and hydrogen peroxide
were used as the reagents. This method has been widely used for
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